Infection with human immunodeficiency virus type 1 (HIV-1), the lentivirus that causes acquired immunodeficiency syndrome (AIDS), is one of the leading causes of death worldwide. Most currently available antiretroviral agents inhibit essential HIV-1 enzymes, either the reverse transcriptase or the protease. Recent advances have markedly improved the outcome for many patients who receive these classes of antiretroviral drugs. However, the success of current therapy is limited by the emergence of drug-resistant viruses, the necessity of sustained adherence to complex regimens and the potential for toxic side effects. Novel classes of safe and effective agents with a low risk of cross-reactivity with other antiretroviral drugs continue to be needed.
It is thought that targeting viral entry may have advantages over the inhibition of steps in the viral life cycle after the cell has been infected (reviewed in Kilby and Eron, N. Engl. J. Med. 348: 2228-2238 (2003)). The HIV-1 envelope glycoprotein is involved in viral entry and consists of two noncovalently associated subunits, a surface glycoprotein (gp120) and a transmembrane glycoprotein (gp41). Portions of gp120 bind to the CD4 receptor and chemokine coreceptors (CXCR4 and CCR5) on target cells (Feng et al., Science 272: 872-877 (1996); Dragic et al., Nature 381: 667-673 (1996); Deng et al., Nature 381: 661-666 (1996)). After gp120-CD4-coreceptor binding, the gp41 subunit undergoes a conformational change that promotes fusion of the viral and cellular membrane, resulting in entry of the viral core into the cell, transport to the nucleus and ultimately, proviral integration and expression (Chan et al., Cell 89: 263-273 (1997)).
The primary amino acid sequence of gp41 includes “heptad-repeat” regions (HR1 and HR2), reflecting the presence of periodic hydrophobic regions found in alpha-helical “coiled-coil” secondary structures (Gallaher et al., AIDS Res. Hum. Retroviruses 5: 431-440 (1989); Delwart et al., AIDS Res. Hum. Retroviruses 6: 703-706 (1990)). HR1 and HR2 form a helical bundle containing three members (a trimer) of each domain (Chan et al., supra; Tan et al., Proc. Natl. Acad. Sci. (USA) 94: 12303-12308 (1997); Weissenhorn et al., Nature 387: 426-430 (1997)). These heptad repeats have a role in the conformational changes essential for membrane fusion of HIV-1 with host cells (Dubay et al., J. Virol. 66: 4748-4756 (1992); Wild et al., Proc. Natl. Acad. Sci. (USA) 91: 12676-12680 (1994)).
Synthetic peptides that mimic HR2 segments of gp41 block fusion and have significant antiretroviral effects (Gallaher et al., supra; Delwart et al., supra; Dubay et al., J. Virol. 66: 4748-4756 (1992)). Two peptides, T-20 and T-1249, have been studied in clinical trials (Wild et al., AIDS Res. Hum. Retroviruses 9: 1051-1053 (1993); Eron et al., J. Infect. Dis. 189: 1075-1083 (2004); reviewed in Kilby and Eron, supra; also reviewed in Jiang et al., Curr. Pharm. Des. 8: 563-580 (2002)).
T-20 (FUZEON® brand of enfuvirtide), a 36-amino-acid peptide derived from the HR2 sequence, has been demonstrated to reduce viral levels in infected patients 1-2 logs in clinical trials (Kilby et al., Nat. Med. 4: 1302-1307 (1998)). This compound is used in combination with existing therapies employing multiple anti-HIV drugs such as highly active anti-retroviral therapy (HAART) and is also used to treat salvage therapy cases, where patients are no longer responsive to their treatment regimen. However, this peptide HIV fusion inhibitor is sensitive to proteolytic digestion and therefore has a short plasma half-life of about 1.8 hours. Consequently, large doses (90 mg/injection) need to be administered twice daily for full efficacy (reviewed in Jiang et al., supra).
In comparison, T-1249, a 39-amino-acid consensus peptide derived from HIV-1, HIV-2 and Simian Immunodeficiency Virus (SIV) gp-41, has an increased, but still relatively short plasma half-life of 9 to 14 hours and also needs to be injected twice daily to sustain effective blood levels (Eron and Hogan, PRN Notebook 7: 16-22 (2002)). Thus, a need exists for improved HIV fusion inhibitors with longer half-lives.